Composite Following the strategic directions proposed by the National Institute on Aging, an overall objective of the proposed research in this program project is to identify genetic and non-genetic factors and mechanisms, which can promote long and healthy life in humans on the basis of better understanding the relationships among regulators of aging, risks, of major diseases and related traits, and lifespan. This objective will be reached on the basis of integrative analyses of genome-wide SNP genotyping data and longitudinal data on life course processes in human organisms. The research in this program project will be performed in three subprojects, supported by the (A) Administrative, and (B) Data Management/Analytic Cores. We will use traditional and advanced methodologies of genetic analyses and statistical modeling, and methods of systems biology, which will be built on knowledge accumulated in the fields of aging, health, and lifespan incorporated into the integrative statistical platform. The methodological concept of the POI stands to advance paradigms of current GWAS and future association studies, using next generation sequencing, by bringing state-of-the-art methods to analyzing traits of late life that breaks new ground in the area of life-course genetics. The project will address three Specific Aims. Aim 1. Conduct comprehensive association analyses using genome-wide SNP genotyping data to identify pleiotropic and specific genetic underpinnings of lifespan, risks of major diseases, health related traits, and physiological aging changes in human body. Aim 2. Conduct analysis of up-to-date information on biological effects of pleiotropic and specific genes for SNPs discovered in Aim 1 to dissect their roles in molecular pathways, and biological processes and functions. Aim 3. Perform dynamic integration of genetic effects revealed in Aims 1 and 2 into the life course processes in individuals by combining methods of systems biology and advanced statistical modeling.